Abstract The pathogenesis of Sickle cell disease (SCD) comprises a complex interplay of factors associated with vascular endothelial activation, intense inflammation, and increased sickle cell adhesion. Microvascular occlusion in SCD is initiated by adhesion of sickle red blood cells (RBCs) to the endothelium, leading to acute painful vasoocclusive crisis (VOC) and the clinical morbidity in SCD. Treatment strategies include the use of chronic blood transfusion, hydroxyurea, and bone marrow transplantation but these treatments are not without significant side effects. Because of the inherent complexity of this disease, it is unlikely that a single therapeutic strategy will be beneficial. In this Phase I Application we propose to study a sulfated oxidized non-anticoagulant low molecular weight heparin (LMWH), referred to as S-NACH, with an extensive range of bioactivities that constitute a multi-modal approach to management of SCD. Of significant importance to the development of this agent is the fact that S-NACH exerts these activities without causing hemostatic (bleeding) side effects that are associated with the clinical use of LMWHs. Additionally, S-NACH has been optimized to directly interact with hemoglobin to exert desirable therapeutic benefits. LMWHs have been tested for clinical management of VOC in SCD, and we have previously shown that LMWH tinzaparin significantly shortened both duration of VOC crisis and hospitalization by ~40% and resulted in significant and more rapid reduction of pain. However, despite the demonstrated potential benefits of LMWHs for SCD, safety concerns associated with the narrow therapeutic index (bleeding risks) are a major barrier to dose escalation/optimization of treatments. Consequently, further studies are clearly warranted. Our novel multi-modal compound S-NACH provides the opportunity to pursue studies that will conclusively establish safety and efficacy. In this proposal, we will perform proof-of-concept in vitro and in vivo pre-clinical studies, which would expand on our rich body of pilot data and establish efficacy in a mouse model of SCD, and lay critical foundation for the potential advancement of this agent to clinical applications. Upon successful completion, we will, in Phase II studies, rigorously explore various formulations of S-NACH (including oral nano- formulations), geared towards feasible administration in acute and chronic situations; conduct GLP scale up; conduct x-ray crystallography studies to ascertain the detailed nature of interactions of S-NACH with Hb, and utilize gained knowledge to further optimize design and synthesis for efficacy and specificity; conduct safety and efficacy studies in preclinical models for the advancement for acute and chronic disease management in SCD patients.